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Manufacturing biosensors
Biosensors & Bioelectronics 7 (I 992) 16l- 163
MANUFACTURING BIOSENSORS W.J. Aston Once it has been confirmed that a market exists for a biosensor and that it can be economically and consistently produced to the quality needed to satisfy the market requirements, manufacturing may begin. This article addresses some of the issues, such as safety and packaging, that need to be considered early in the development process before large-scale production starts.
SAFETY ISSUES Large-scale production can introduce safety problems. For example, the handling during production and subsequent disposal of waste solvents can become major issues when large-scale manufacturing is undertaken and can have a significant impact on a manufacturing scenario. Increased volumes of solvents used in the doping of electrodes described in the previous article in this series (Aston, 1992) would have had serious implications for safety and would be a major concern for most companies, even well established ones. The installation of air conditioning, clean room and other specialist requirements can be a significant cost in the setting-up of an operation. Part of this cost involves ensuring that the facilities can be maintained to the correct degree of cleanliness, the actual specification being dependant on the standard to which the product has to comply. Dr W.J. Aston is Director of New Ventures at Cranfield Biotechnology Ltd, Bedford MK43 OAL, UK, which offers a range of services to companies including the protection of intellectural property, market surveys, research, design, and development, through to prototype assembly and manufacture. He was fomerly General Manager of MediSense UK, and was involved in all aspects of the commercialization of the mediated amperometric biosensor ‘ExacTech’marketed for use by diabetics.
0956-5663/92/$05.00
01992
For operators to work in areas in which solvents are used, it is necessary to ensure that the vapours are removed and vented. Their removal and the replacement of the air to the atmosphere can result in considerable costs, and the installation of heat-exchange units at a later date is usually highly disruptive.
SHELF-LIFE AND PACKAGING Moisture has a significantly detrimental effect on the shelf-life of a biosensor. This effect can be easily observed if strip devices are retained in a high humidity environment, and their linear response tested with time. When a glucose biosensor, for example, is challenged with solutions of glucose, the response decreases dramatically with time. This has significant implications for distribution. The majority of distributors will only accept products that have a minimum shelf life of 18 months, which allows a number of processes to be completed. These include post-production operations such as calibration of the electrodes before distribution to the retailer and stores. Although retailers will accept products with limited shelf lives while they are evaluating the demand from their customers, they do not want to stock unstable products. Packaging of self-testing diagnostic devices is performed in environments that have low
Elsevier Science Publishers Ltd.
161
Biosensors & Bioelectronics
humidity. The installation of a low-humidity environment affects the cost of setting up facilities significantly. These costs can be reduced by the installation of localized air handling units. To maintain the shelf-life of products, diagnostics companies maintain the product in as dry a form as possible by adopting one of two main types of packaging. In the first products involving calorimetric strips, introduced by Boehringer Mannheim and Miles Bayer, products were placed in desiccated containers, the desiccant typically being incorporated within the lid. MediSense Inc maintains its product at low humidity by packaging each individual biosensor at low humidity in a discrete foil sachet. Using individual packaging eliminates the risk that unused electrodes will be inactivated if the lid is accidently left off a container for a prolonged period of time. All manufacturers maintain the orientation of the product within the package so that they can be easily removed without handling the area on which the blood is placed before use.
lead to high rejection rates and excessive manufacturing costs. The development process should not rely on the results of one batch of materials. In an extreme example of the pitfalls of this approach, a US-based UK diagnostics company was developing a antibody-based assay using the antibodies produced from’a single sheep. The project proceeded on schedule with all the development objectives being met, until the sheep died. The company then tried to obtain an alternative source of antibodies but none of the sheep tested produced any that were suitable. The use of a single batch of mediator could have the same profound effect on a biosensor development project. Variations in component specifications can greatly affect the final product, and the specific activity of the enzyme affects the response when the system is challenged with a solution that contains the metabolite.
SIZE AND LAYOUT OF FACILITIES AVAILABLITY OF COMPONENTS The cost and availability of materials can have a profound influence on the development of a product and the cost of manufacturing. Preliminary studies involving the use of biosensors to analyse methanol in drinking water used the enzyme methanol dehydrogenase (Aston et al., 1984). The enzyme was not commercially available and considerable time and effort was necessary to develop a technique that would allow sufficient quantities to be produced (Best and Aston, 1985). On the other hand, the enzyme glucose oxidase is a by-product of a fermentation reaction, and is commercially available in large quantities from a range of suppliers. The setting up of dedicated equipment or customized manufacture of specific enzymes can make it harder to satisfy market demands. During the development phase, it is important to determine the maximum tolerances for each of This is to ensure that the components. manufacturing is not restrained by tight and inappropriate specifications, both for incoming raw materials and inprocess materials, as these
162
The majority of companies in the diagnostics industry lease small units in which to commence development operations and later expand into additional premises as the operation progresses. In the UK, MediSense started operations by leasing small premises close to Oxford to undertake initial product development. As development progressed, it leased additional premises, which were used for the pilot plant facilities and subsequently the main manufacturing facility. With a stepwise acquisition of premises, the company was able to concentrate its effort on development while minimizing the financial risk in the premises. Compartmentalizing facilities in this way allows a higher degree of control to be maintained. If a facility is allowed to expand without proper control as demand increases, major problems can be encountered. Consider the process shown in Figure 1, in which a product is assembled. As the demand increases, the company can either develop a duplicate system, expand the existing system or replan for a more efficient operation. Unless care is taken at this stage, the amount of energy and time wasted in
Bioseqsors & Bioelectronics
Figure
1: ProductionJow process for biosensor manufacture.
moving products between the different production stages can be substantial.
THE PRODUCTION PROCESS Production processes are categorized into one of three forms: job, batch and flow. None of these categories can be associated with a particular volume of production, and in certain circumstances the same task can be undertaken by any of the methods. The type of production determines the organizational system used and, to a large extent, the layout of the system. It is rare to find any one unit using only one type of production process; more frequently a mixture of processes depending on the operation being performed will be in place. Job production is the manufacture of a single unit by an operator or a group of operators. In this system the operators must be capable of performing all tasks. As the complexity of the operations increase, the skills required to undertake them increase as well. This leads to batch production, in which some degree of specialization is possible although careful planning is needed. Batch production is characterized by organizational difficulties.
Batch production turns to flow production when the rest periods are removed. Flow production has the advantage of improving material flow, reducing the requirement for skills and adding value fast. Each operation must be of equal length with no removal of the product from the production line. Since the whole system is based on balance, any faults affect all stages in the production line. This mode of operation is inherently inflexible and cannot accommodate variations in the production process. The term mass production can be applied to any of the three methods and is nothing more than production on a large scale. It is sometimes assumed that the mass production of biosensors is associated with low quality; however, mass-produced products are usually of uniform quality. Provided the process is under control, quality is dependant on managerial policy and not the scale of production.
FUTURE RESEARCH AND DEVELOPMENT In most cases, inventions in the diagnostics area arise as a result of scientists trying to achieve a prespecified objective. In some instances, this can result in the product becoming over-engineered with the result that it can only be produced by skilled individuals or by the development scientists themselves. This would produce a company with a single labourexpensive product and a limited ability to develop subsequent products. Over a period of time, this would result in the company losing its key scientific staff, often to its competitors. It is only by continued investment into new products that a company can maintain its competitive edge. However, too much investment in research too early in the company’s growth can use up vital resources and diminish the chance of success.
REFERENCES Aston, W.J., Ashby, R.E.A., Higgins, I.J.H., Scott, L.D.L. &Turner, A.P.F. (1984). Enzyme based methanol sensor. In Charge and field effects in biosystems, edited by M.J. Allen and P.N.R. Usherwood, published by Abacus Press. Aston, W.J. (1992). Product design and development.
Biosensors & Bioelectronics, 7, 85-89.
Best, D.J. and Aston, W.J. (1985). Rapid purification of methanol dehydrogenase by aqueous partition. 4th International Symposium on Microbial Growth on C 1 Compounds in Minneapolis, Minnesota, USA.
163
MANUFACTURING BIOSENSORS W.J. Aston Once it has been confirmed that a market exists for a biosensor and that it can be economically and consistently produced to the quality needed to satisfy the market requirements, manufacturing may begin. This article addresses some of the issues, such as safety and packaging, that need to be considered early in the development process before large-scale production starts.
SAFETY ISSUES Large-scale production can introduce safety problems. For example, the handling during production and subsequent disposal of waste solvents can become major issues when large-scale manufacturing is undertaken and can have a significant impact on a manufacturing scenario. Increased volumes of solvents used in the doping of electrodes described in the previous article in this series (Aston, 1992) would have had serious implications for safety and would be a major concern for most companies, even well established ones. The installation of air conditioning, clean room and other specialist requirements can be a significant cost in the setting-up of an operation. Part of this cost involves ensuring that the facilities can be maintained to the correct degree of cleanliness, the actual specification being dependant on the standard to which the product has to comply. Dr W.J. Aston is Director of New Ventures at Cranfield Biotechnology Ltd, Bedford MK43 OAL, UK, which offers a range of services to companies including the protection of intellectural property, market surveys, research, design, and development, through to prototype assembly and manufacture. He was fomerly General Manager of MediSense UK, and was involved in all aspects of the commercialization of the mediated amperometric biosensor ‘ExacTech’marketed for use by diabetics.
0956-5663/92/$05.00
01992
For operators to work in areas in which solvents are used, it is necessary to ensure that the vapours are removed and vented. Their removal and the replacement of the air to the atmosphere can result in considerable costs, and the installation of heat-exchange units at a later date is usually highly disruptive.
SHELF-LIFE AND PACKAGING Moisture has a significantly detrimental effect on the shelf-life of a biosensor. This effect can be easily observed if strip devices are retained in a high humidity environment, and their linear response tested with time. When a glucose biosensor, for example, is challenged with solutions of glucose, the response decreases dramatically with time. This has significant implications for distribution. The majority of distributors will only accept products that have a minimum shelf life of 18 months, which allows a number of processes to be completed. These include post-production operations such as calibration of the electrodes before distribution to the retailer and stores. Although retailers will accept products with limited shelf lives while they are evaluating the demand from their customers, they do not want to stock unstable products. Packaging of self-testing diagnostic devices is performed in environments that have low
Elsevier Science Publishers Ltd.
161
Biosensors & Bioelectronics
humidity. The installation of a low-humidity environment affects the cost of setting up facilities significantly. These costs can be reduced by the installation of localized air handling units. To maintain the shelf-life of products, diagnostics companies maintain the product in as dry a form as possible by adopting one of two main types of packaging. In the first products involving calorimetric strips, introduced by Boehringer Mannheim and Miles Bayer, products were placed in desiccated containers, the desiccant typically being incorporated within the lid. MediSense Inc maintains its product at low humidity by packaging each individual biosensor at low humidity in a discrete foil sachet. Using individual packaging eliminates the risk that unused electrodes will be inactivated if the lid is accidently left off a container for a prolonged period of time. All manufacturers maintain the orientation of the product within the package so that they can be easily removed without handling the area on which the blood is placed before use.
lead to high rejection rates and excessive manufacturing costs. The development process should not rely on the results of one batch of materials. In an extreme example of the pitfalls of this approach, a US-based UK diagnostics company was developing a antibody-based assay using the antibodies produced from’a single sheep. The project proceeded on schedule with all the development objectives being met, until the sheep died. The company then tried to obtain an alternative source of antibodies but none of the sheep tested produced any that were suitable. The use of a single batch of mediator could have the same profound effect on a biosensor development project. Variations in component specifications can greatly affect the final product, and the specific activity of the enzyme affects the response when the system is challenged with a solution that contains the metabolite.
SIZE AND LAYOUT OF FACILITIES AVAILABLITY OF COMPONENTS The cost and availability of materials can have a profound influence on the development of a product and the cost of manufacturing. Preliminary studies involving the use of biosensors to analyse methanol in drinking water used the enzyme methanol dehydrogenase (Aston et al., 1984). The enzyme was not commercially available and considerable time and effort was necessary to develop a technique that would allow sufficient quantities to be produced (Best and Aston, 1985). On the other hand, the enzyme glucose oxidase is a by-product of a fermentation reaction, and is commercially available in large quantities from a range of suppliers. The setting up of dedicated equipment or customized manufacture of specific enzymes can make it harder to satisfy market demands. During the development phase, it is important to determine the maximum tolerances for each of This is to ensure that the components. manufacturing is not restrained by tight and inappropriate specifications, both for incoming raw materials and inprocess materials, as these
162
The majority of companies in the diagnostics industry lease small units in which to commence development operations and later expand into additional premises as the operation progresses. In the UK, MediSense started operations by leasing small premises close to Oxford to undertake initial product development. As development progressed, it leased additional premises, which were used for the pilot plant facilities and subsequently the main manufacturing facility. With a stepwise acquisition of premises, the company was able to concentrate its effort on development while minimizing the financial risk in the premises. Compartmentalizing facilities in this way allows a higher degree of control to be maintained. If a facility is allowed to expand without proper control as demand increases, major problems can be encountered. Consider the process shown in Figure 1, in which a product is assembled. As the demand increases, the company can either develop a duplicate system, expand the existing system or replan for a more efficient operation. Unless care is taken at this stage, the amount of energy and time wasted in
Bioseqsors & Bioelectronics
Figure
1: ProductionJow process for biosensor manufacture.
moving products between the different production stages can be substantial.
THE PRODUCTION PROCESS Production processes are categorized into one of three forms: job, batch and flow. None of these categories can be associated with a particular volume of production, and in certain circumstances the same task can be undertaken by any of the methods. The type of production determines the organizational system used and, to a large extent, the layout of the system. It is rare to find any one unit using only one type of production process; more frequently a mixture of processes depending on the operation being performed will be in place. Job production is the manufacture of a single unit by an operator or a group of operators. In this system the operators must be capable of performing all tasks. As the complexity of the operations increase, the skills required to undertake them increase as well. This leads to batch production, in which some degree of specialization is possible although careful planning is needed. Batch production is characterized by organizational difficulties.
Batch production turns to flow production when the rest periods are removed. Flow production has the advantage of improving material flow, reducing the requirement for skills and adding value fast. Each operation must be of equal length with no removal of the product from the production line. Since the whole system is based on balance, any faults affect all stages in the production line. This mode of operation is inherently inflexible and cannot accommodate variations in the production process. The term mass production can be applied to any of the three methods and is nothing more than production on a large scale. It is sometimes assumed that the mass production of biosensors is associated with low quality; however, mass-produced products are usually of uniform quality. Provided the process is under control, quality is dependant on managerial policy and not the scale of production.
FUTURE RESEARCH AND DEVELOPMENT In most cases, inventions in the diagnostics area arise as a result of scientists trying to achieve a prespecified objective. In some instances, this can result in the product becoming over-engineered with the result that it can only be produced by skilled individuals or by the development scientists themselves. This would produce a company with a single labourexpensive product and a limited ability to develop subsequent products. Over a period of time, this would result in the company losing its key scientific staff, often to its competitors. It is only by continued investment into new products that a company can maintain its competitive edge. However, too much investment in research too early in the company’s growth can use up vital resources and diminish the chance of success.
REFERENCES Aston, W.J., Ashby, R.E.A., Higgins, I.J.H., Scott, L.D.L. &Turner, A.P.F. (1984). Enzyme based methanol sensor. In Charge and field effects in biosystems, edited by M.J. Allen and P.N.R. Usherwood, published by Abacus Press. Aston, W.J. (1992). Product design and development.
Biosensors & Bioelectronics, 7, 85-89.
Best, D.J. and Aston, W.J. (1985). Rapid purification of methanol dehydrogenase by aqueous partition. 4th International Symposium on Microbial Growth on C 1 Compounds in Minneapolis, Minnesota, USA.
163